Tanimura S M, Watts A G
Department of Biological Sciences, University of Southern California, Los Angeles 90089-2520, USA.
Endocrinology. 1998 Sep;139(9):3830-6. doi: 10.1210/endo.139.9.6192.
We have used in situ hybridization to investigate how basal levels of circulating corticosterone modulate CRH gene transcription in the neuroendocrine parvicellular part of the hypothalamic paraventricular nucleus (PVHmpd) during sustained hypovolemia. In the absence of the stressor, the accumulation rate of the CRH primary transcript exhibited a dose dependency on low maintained levels of plasma corticosterone similar to that previously reported for the mature messenger RNA (mRNA); levels declined as plasma corticosterone increased. In response to hypovolemia, the absence of corticosterone compromised CRH gene transcription mechanisms to mount the activated response seen in intact animals. However, adrenalectomized rats with low doses of corticosterone (insufficient to normalize thymus weights) showed an augmented mRNA response compared with that in intact animals. When replaced corticosterone normalized thymus weights, the magnitude of the mRNA response was reduced to that seen in intact animals. In contrast to CRH gene regulation, PVHmpd proenkephalin mRNA levels were unaffected by corticosterone concentrations. These results suggest that corticosterone affects CRH gene transcription in the PVHmpd using two mechanisms: first, inhibition, which probably uses type II glucocorticoid receptor-dependent mechanisms and contributes to classic negative feedback; and second, facilitation, which is seen at low plasma concentrations and maintains gene transcription in the presence of sustained stress, possibly using type I mechanisms. This suggests that one reason why adrenal insufficiency severely compromises survival of sustained stress is that CRH gene transcription cannot be maintained without previous exposure to low levels of plasma corticosterone.
我们利用原位杂交技术研究了在持续性血容量不足期间，循环皮质酮的基础水平如何调节下丘脑室旁核神经内分泌小细胞部分（PVHmpd）中促肾上腺皮质激素释放激素（CRH）基因的转录。在没有应激源的情况下，CRH初级转录本的积累速率对低水平维持的血浆皮质酮呈现剂量依赖性，类似于先前报道的成熟信使核糖核酸（mRNA）的情况；随着血浆皮质酮水平升高，其水平下降。对血容量不足的反应中，缺乏皮质酮会损害CRH基因转录机制，无法产生完整动物中所见的激活反应。然而，低剂量皮质酮（不足以使胸腺重量恢复正常）的肾上腺切除大鼠与完整动物相比，mRNA反应增强。当补充皮质酮使胸腺重量恢复正常时，mRNA反应的幅度降低至完整动物中的水平。与CRH基因调节不同，PVHmpd脑啡肽原mRNA水平不受皮质酮浓度影响。这些结果表明，皮质酮通过两种机制影响PVHmpd中的CRH基因转录：第一，抑制作用，可能利用II型糖皮质激素受体依赖性机制，参与经典的负反馈；第二，促进作用，在低血浆浓度时可见，在持续应激存在时维持基因转录，可能利用I型机制。这表明肾上腺功能不全严重损害持续应激下生存的一个原因可能是，没有先前暴露于低水平血浆皮质酮，CRH基因转录就无法维持。
